Herpes simplex virus (HSV) is the leading cause of infectious blindness in the industrialized nations. In the USA, 300,000 cases are treated yearly. Ocular HSV causes a self-limiting epithelial keratitis, blepharitis, con- junctivitis, stromal keratitis, and the most damaging disease, necrotizing herpetic stromal keratitis (HSK). HSK is the most difficult to manage; about half of the patients do not respond to combination chemotherapy and will have significant loss of vision or blindness. HSV is a neurotrophic virus characterized by its ability to establish lifelong latency in neurons and to reactivate at peripheral sites, causing recurrent disease. The ocular recur- rences cause significant corneal scarring, leading to HSK. Our proposal will examine the relationship between low and high HSV-1 phenotypic reactivators in a mouse model highly susceptible to ocular pathogenesis. The e4 allele of Apolipoprotein E (ApoE) is a risk factor for ocular herpes. We will demonstrate that different phenotypes (strains) of HSV have different ocular pathogenesis in e4 knock-in mice, a transgenic mouse strain created by insertion of the human ApoE gene into a trans- genic mouse from which the mouse ApoE gene was removed. We will evaluate two ApoE mimetic receptor- based peptides that separately exhibit anti-viral and anti-herpetic activity in a combination therapy to treat the severe ocular pathogenesis resulting from HSV-1 infection in e4 mice. We hypothesize that our investigation using the two ApoE peptides will document a reduction in ocular pathogenesis and oxidative damage in neurons and epigenetic control that is affected by this therapy. To this end, we plan to follow these Specific Aims: Specific Aim 1: To test the hypothesis that significant differences in ocular pathogenesis will occur in e4 mice when infected with high and low phenotypic reactivating strains of HSV-1. Specific Aim 2: To test the hypothesis that more pathogenesis will occur when ApoE e4 mice latently infected with the high phenotypic reactivator are induced to reactivate than in those latently infected with the low phenotypic reactivator. Specific Aim 3: To test the hypothesis that therapy with two unique ApoE peptides will successfully inhibit the induction of HSV-1 reactivation of the high phenotypic reactivator in ApoE e4 mice. These studies, if successful, will demonstrate 1) the role of contrasting HSV-1 phenotypic strains in ocular herpes, 2) the susceptibility and increased pathogenesis of the e4 allele carrier using mice latent with a high phenotypic reactivator and given an HSV-1 induction stimulus, and 3) that two ApoE peptides can inhibit HSV- 1 reactivation and ocular pathogenesis, even in highly susceptible e4 mice that are given an HSV-1 inducer. These pharmacological studies will offer the possibility of a new combination therapy for patients with ocular herpes and possibly for other HSV diseases such as encephalitis and genital herpes. These studies involving translational research, epigenetics, and ocular pathogenesis are in accordance with the research goals of the December 2006 National Plan for Eye and Vision Research. PUBLIC HEALTH RELEVANCE: Herpes Simplex Virus (HSV) is the leading cause of infectious, non-traumatic blindness in all industrialized nations, with over 300,000 cases treated in the United States per year. While therapies are available, some patients remain strongly resistant to current treatments, thus our research targets a specific human gene, the e4 allele of apolipoprotein E (ApoE), which has been implicated in the pathogenesis of ocular HSV- 1. The use of two receptor-based ApoE mimetic peptides that exhibit potent anti-viral and anti-inflammatory activity, and which act to suppress this gene, holds great promise as a new therapy for ocular and other HSV-related diseases.